Final exam (3) Flashcards
1
Q
Metabolic disease types
A
1.) Genetic diseases: neuronal storage diseases, mitochondrial encephalomyopathies, leukodystrophies
2.) Toxic and acquired: vitamin deficiencies, metabolic and toxic disturbances
2
Q
Neuronal storage diseases
A
- autosomal recessive diseases caused by a deficiency of a specific enzymes involved in the metabolism
- defect leads to the accumulation of the substrate of the enzyme withing the lysosomes of neurons resulting in neuronal death
- commonly: neuronal ceroid lipofuscinoses, Tay-Sachs
3
Q
Neuronal Ceroid Lipofuscinoses (NCLs)
A
- Batten disease
- group of neurodegenerative disorders
- Lipofuscin accumulates within neurons leading to dysfunction
- Symptoms: blindness, mental and motor deterioration, seizures
- all clinical subtypes involve CLN genes affecting the lysosomes
4
Q
Lipofuscin
A
- yellow-brown, granular, iron-negative lipid pigment found in muscle, heart, liver, and nerve cells
- it is the product of cellular wear and tear, accumulating in the lysosomes with age
5
Q
Tay-Sachs disease
A
- Autosomal recessive
- Deficiency of Hexaminidase A
- accumulation of ganglioside in all tissues
- usually begins in early infancy, death within several years
- Developmental delay, and then paralysis and loss of neurologic function
6
Q
Tay Sachs features
A
T-esting recommended
A-utosomal recessive
Y-oung death (<4 years)
S-pot in the macula (cherry red spot)
A-shkenazi jews
C-NS degeneration
H-ex A deficiency
S- torage disease
7
Q
GM2 metabolism in Tay Sachs
A
Hex A not present –> GM2 accumulates (cell-cell signalers, lipid rafts) –> neuronal death
8
Q
Krabbe disease
A
- autosomal recessive
- decrease in GALC, increase in psychosine and globoid cells
- Deficiency in galactocerebroside B-galactosidase that catabolizes galactocerebrosidases to ceramide and galactose
- alternative pathway generates galactosylsphingosine and which causes oligodendrocyte
- rapidly progressive clinical course with onset of symptoms between 3-6 months. survival beyond age 2 is uncommon
9
Q
Krabbe disease symptom pathology
A
- Motor signs: stiffness and weakness
- Loss of myelin and oligodendrocytes in CNS and peripheral nerves, sparing of neurons and axons
- Aggregation of macrophages filled with cerebroside forming multi-nucleated globoid cells around blood vessels
10
Q
Mitochondrial encephalomyopathies
A
- many inherited disorders of mitochondrial oxidative phosphorylation present as muscle disease
- Leigh syndrome, myoclonic epilepsy, and ragged red fibers (MERRF)
11
Q
Thiamine Vitamin B1 deficiency
A
- Beri beri
- Wernicke’s encephalopathy: psychotic symptoms or opthalmplegia that begins abruptly
- Korsakoff syndrome: memory disturbances and confabulation
- important cause of B1 deficiency: chronic alcoholism and gastric disorders
12
Q
Wernicke encephalopathy
A
- Foci of hemorrhage and necrosis in the mammillary bodies and adjacent to the ventricle
- hemorrhagic areas are infiltrated by macrophages and form cystic spaces
13
Q
Korsakoff syndrome
A
- hemosiderin laden lesions predominate, including the medial dorsal nucleus of the thalamus (executive fxn, PFC) correlating to clinical symptoms of memory disturbances and confabulation
14
Q
Vitamin B12 deficiency
A
- a cofactor in myelin formation and important immunomodulatory and neutrophilic effects
- neuro symptoms: ataxia, numbness and tingling in lower extremities, may progress to spastic weakness of lower extremities
- histology: swelling of myelin layers, producing vacuoles that begin at midthoracic level of spinal cord –> degeneration of posterior and pyramidal tracts
15
Q
Hypoglycemia
A
- causes neurological sequelae
- selective injury to the large pyramidal neurons of the cerebral cortex, hippocampus, purkinje cells of the cerebellum
16
Q
Hyperglycemia
A
- causes neurological sequelae
- in diabetes mellitus: patient becomes dehydrated and develops confusion, stupor, and eventually coma. Gradual correction of fluid depletion to prevent severe cerebral edema
17
Q
Hepatic encephalopathy
A
- Causes neurologic sequelae
- chronic hepatitis, Reye’s syndrome, or cirrhosis ( a damaged liver does not remove toxins from the blood)
- Glial cell response: Alzheimer type 2 astrocytes (non-neural glial cell)
18
Q
Carbon monoxide
A
- pathological findings are a result of hypoxia
- injury of neuron layers 3 and 5 of the cerebral cortex, Sommer sector of hippocampus, and Pukinje cells
- Bilateral necrosis of the globus pallidus
- During the first few hours, the brain becomes swollen, congested, and cherry red
19
Q
Ethanol
A
- direct effects of secondary to nutritional deficits
- Cerebellar dysfunction in 1% chronic alcoholics: truncal ataxia, unsteady gait, nystagmus
- Histology: atrophy and loss of purkinje cells in the anterior vermis
20
Q
Amphetamine drugs
A
DL-amphetamine: Adderall, speed
Dextroamphetamine: more potent D-isomer of amphetamine, Dexedrine
Methamphetamine: Crystal meth
21
Q
Amphetamine pharmacological effects
A
- release monoamines, primarily norepinephrine and dopamine, from nerve terminals to brain
- Substrates for the neuronal monoamine uptake transporters NET and DAT (not SERT)
- enter sympathetic nerve endings and displace stored NE and DA, interact with VMAT-2 (vesicular monoamine pump), and inverses reuptake transporters to push out more NTs
22
Q
At high concentrations, amphetamines inhibit
A
monoamine oxidase (MAO) (breaks down DA and NE)
23
Q
Pharmacological effects of amphetamines
A
- locomotor stimulation
- euphoria and excitement
- insomnia
- increased stamina
- anorexia (short term)
- feelings of anxiety, irritability, and restlessness
- high doses may create panic and paranoia
Peripheral effects: rise in blood pressure, inhibition of GI motility
24
Q
Amphetamine prolonged misuse
A
- Amph. psychosis
- acute schizophrenic attack
- repetitive stereotyped behavior
- antipsychotics are effective
- once drug is stopped: period of deep sleep, lethargy, depression, anxiety, suicidal, hungry
25
Amphetamines create strong psychological:
dependence. Insistent memory of euphoria
- First dose: increased as tolerance develops
- Uncontrolled binge of the drug
- Large doses consumed: lethal
- animal models: unlimited access --> take such large amounts they die
- limited --> develop a binge pattern of dependence
26
methylphenidate (Ritalin)
- inhibits the NET and DAT transporters (inhibits SERT but lower potency)
- NOT a substrate for NET/DAT transporters
- significant and sustained elevation of extracellular NE and DA
- Orally active, absorbed from the intestine and colon, metabolized by carboxylesterase (2-4 hr half life)
27
Modafinil
- atypical stimulant, structurally unrelated to amphetamine
- increases extracellular DA levels in striatum and nucleus accumbens (likely inhibits DA reuptake by binding to DAT)
- enhanced release of 5-HT, glutamate and histamine and inhibits GABA release
- well absorbed from the gut, metabolized in the liver and has a half-life of 10-14 hours
28
Modafinil effects and side effects
- promoted as wakefulness promoting agent rather than a classic amphetamine-like stimulant, brightens mood but no euphoria
- not used for children because of Stevens-Johnson syndrome)
29
MDMA (ecstasy)
- party drug
- Euphoria, loss of inhibitions, and energy surge that it induces
- Stimulant + mild hallucinogenic effects
- Psychotomimetics- affect thought, perception and mood
- Feelings of empathy and emotional closeness to others (empathogen) -- potentially used for treatment of PTSD
30
MDMA pharmacological effects
- monoamine transporter substrate, especially 5-HT transporter (but also NE and DA transporters), competitive inhibition of 5-HT reuptake, and reverses transporters
- promotes 5-HT release --> followed by monoamine depletion
31
MDMA effects and side effects
- Acute hyperthermia --> damage to skeletal muscle and consequent renal failure
- may be an exacerbation by energetic dancing and high ambient temperature
- may reflect an action of MDMA on mitochondrial function (?)
- excess water intake and retention (increased ADH and thirst--> hyponatremia--> coma)
32
MDMA can lead to sudden illness and death in which population?
undiagnosed heart conditions-- heart failure can occur
33
After-effects of MDMA
- depression, anxiety, irritability, and increased aggression
- long-term deleterious effects on memory and cognitive function in heavy MDMA users
34
Cocaine
- Binds to and inhibits the transporters NET, DAT, and SERT to cause marked psychomotor stimulant effect
- Peripheral action: tachycardia, vasoconstriction, increased blood pressure
35
Overdose symptoms of cocaine
- tremors
- convulsions
- respiratory and vasomotor depression
36
Hydrochloride salt: nasal inhalation or IV
- cocaine
- intense and immediate euphoria with IV
- nasal inhalation less dramatic, atrophy and necrosis of the nasal mucosa and septum
37
Crack cocaine- smoked, vaporizes at 90 degrees celcius
- unchanged free-base form, not soluble in water
- rapidly absorbed across the large surface area of the alveoli
- effect nearly as rapid as IV injection
38
When is cocaine used as a topic local anesthetic?
- ophthalmology and minor nose and throat surgery
- local vasoconstrictor action
39
Adverse effects of cocaine
- Cardiac dysrhythmias
- Aortic dissection
- myocardial/ cerebral infarction or hemorrhage
- can lead to heart failure even without hx of acute cardiac events
40
Atomoxetine (strattera)
- highly selective NE reuptake inhibitor
- does not increase DA levels in striatum/nucleus accumbens (abuse liability gone)
- only ADHD medication that has no abuse potential
- Black box warning- increase SI/thoughts
- SE: nausea, vomiting, weight loss, sleep problems, liver damage
41
ADHD
- co-existence of inattentiveness, hyperactivity, impulsivity
- symptoms start before 7 years of age, with at least 6 attention symptoms or 6 hyperactive/impulsivity symptoms for at least 6 months in two or more settings
42
Neurotransmitters of ADHD
- Prefrontal (NE) and mesocortical (DA) pathways are involved in maintaining and focusing attention
- raising levels of DA and NE should reduce symptoms
43
Drugs for ADHD
- Dexedrine (d-amphetamine)
- Adderall (d, l-amphetamine)
- Ritalin (methylphenidate)
- Focalin (d-methylphenidate)
- Metadate CD (methylphenidate)
- Concerta (Methylphenidate)
44
Narcolepsy
- Rare, disabling, sleep disturbance
- sudden, unpredictable sleep during the day, nocturnal insomnia
- amphetamine and Modafinil helpful interventions
45
Methylxanthines
- Caffeine (coffee)
- Theophylline (tea)
- Theobromine (cocoa)
46
Pharmacological effects of Methylxanthines
- CNS stimulation, block phosphodiesterases --> increased intracellular cAMP
- antagonist of adenosine (A1 and A2 receptors- A2 more important for stimulant effect)
- Diuresis- vasodilation of afferent glomerular arteriole --> increase GFR
- Stimulation of cardiac muscle
- relaxation of smooth muscle, especially bronchial
- effects resemble beta-adrenoreceptor stimulation
47
What treats apnea in prematurity?
Methylxanthines -- caffeine
48
Theophylline
Methylxanthine used as a bronchodilator in treating severe asthmatic attacks
49
The best exam findings in children will be when
you observe the child when they do not know you are watching. Look for: gross motor skills, fine motor skills, language skills, social skills, cognitive skills and retention
50
Gross motor exam in children
1. Infant: in their parents' arms, head control, ability to weight bear, lying on the bed- muscle tone, ability to roll
2. Toddler: can they stand up in the middle of the floor? squat down? go up on their toes? climb onto the bed?
3. School age: posture, quality of movements- gait, run, skip, etc
51
Tone
- resistance through passive movement
- hypotonia: low tone, Hypertonia: high tone, spasticity
52
Strength
- ability to actively move a muscle against resistance
- Focal, generalized, core, progressive increase/decrease?
53
What is the most common motor abnormality in chidlren?
-Hypotonia
- is physiologically normal in prematurity, up to 28-30 weeks gestational age
- hypotonia with brisk tendon reflexes: central neuro dysfxn
- hypotonia with diminished/absent reflexes: neuromuscular etiology (LMN)
54
Hyptonia symptoms in children
1. Infant: frog-legged position when supine, head lag
2. Toddler: delay in achieving gross motor skills, may see "benign hypotonia of infancy" which is outgrown by age 2
3. School age: W-sit without structural reason to do so, struggles to keep up with peers
55
Hypertonia in children
1. Infant: fisting or thumb in palm- persistent, tight muscles with diaper/clothing changes
2. Toddlers: toe walking, delay in gross motor skills
3. School age: abnormalities in their gait pattern (crouched/scissored walking), posturing
56
Rooting reflex
- stroke near the mouth, baby turns head and opens mouth
- appears at 28 weeks GA
- resolves at 4 months
- Abnormal if it persists
57
Suckling reflex
- Necessary for effective feeding (suck-swallow-breath)
- appears at 32 weeks GA, good by 36 weeks GA
- evolves into voluntary suckling
- abnormal if biting, chewing, tongue thrust, uncoordinated with swallow
58
Moro reflex
- Hand open, arms extend (startle reaction)
- appears at 32 weeks GA
- resolves between 4-6 months
- abnormal if asymmetric, triggered too easily, not present
59
ATNR reflex
- Fencing posture (Heisman)
- Appears at 1 month
- resolves at 3-4 months
- abnormal if asymmetric, or persistent
60
Stepping reflex
- positive predictor for walking
- appears at 32 weeks GA
- resolves at 1-2 months
- abnormal if persistent or absent
61
Grasping reflex
- palmer and plantar
- appears at 32 weeks GA for both
- Palmer disappears at 3 months
- plantar disappears at 6 months
- abnormal if absent or persistent
62
Galant reflex
- Stroke next to the spine, trunk curves
- appears at birth
- resolves at 4-6 months
- abnormal if asymmetric
63
Babinski reflex
- stroke bottom of the foot and big toe extends
- can be physiologic at birth
- resolves around 24 months
- abnormal if persistent or unilateral
64
Deep tendon reflexes
- Biceps, C5
- Brachioradialis, C6
- Triceps, C7
- Patellar, L4
- Medial hamstring, L5
- Achilles, S1
- superficial abdomen, T8-T12
65
General exam skills specific to children
- Head circumference
- Palpate the head, fontanelles and sutures
- look for dysmorphisms (facial, body)
- spine check
- skin check (lumbar region)
- stick out their tongue to check for fasciculations, deviations, etc
66
Testing cranial nerves in children
- Visual acuity, fundoscopy, auditory fxn
- facial asymmetry, ability to visually tack, ability to protrude the tongue in the midline, symmetric movement of the soft palate
67
What are we checking on the spine of a child?
- Scoliosis (neuromuscular vs vertebral anomaly)
- Lordosis
- sacral dimple
- Hairy patch
- Skin lesions or vascular formation over the midline
- all concerns for a tethered cord
68
What are we checking for on the skin of a child?
- Cafe au lait (darker patch, NF1)
- Ash leaf (lighter patch, Tuberous sclerosis)
- Port wine (Sturge Weber)
- Hypomelaninosis of Ito
69
Genetic tests possible for identifying disorders
- Karyotyping
- Microarray/comparative genomic hybridization (CGH)
- Focused genetic testing, panels (ex. seizure panel)
- Whole exome sequencing (WES)
70
NF1
- cafe au lait spots, neurofibromas
- autosomal dominant
- optic gliomas
71
NF2
- predisposes individuals to multiple tumors of the nervous system
- bilateral vestibular schwannomas
- autosomal dominant, with multiple manifestations
72
Tuberous sclerosis
- variable expression
- multiple benign hamartomas of the brain, eyes, heart, lung, liver, kidney, and skin
- ASH LEAF spots, shagreen patches, angiofibromas
- autosomal dominant, genetic factors: TSC1 and TSC2
73
Sturge Weber
- rare congenital vascular disorder characterized by a facial capillary malformation (port wine stain)
- associated capillary-venous malformations affecting the brain and eye
- NOT HERITABLE, GNAQ gene affected after conception
- Neuro/ophtho progressive features: seizures, focal neuro deficits, intellectual disability, visual field defects, glaucoma
74
Von Hippel Lindau
- Characteristic benign and malignant tumors, in particular hemangioblastomas of the brain (cerebellum) and spine
- Retinal capillary hemangiomas
- Clear cell renal cell carcinoma (RCCs)
- pheochromocytomas
- endolympathic sac tumors of the middle ear
- Serous cystadenomas and neuroendocrine tumors of the pancreas
- papillary cystadenomasof the epididymis and broad ligament
- autosomal dominant VHL gene
75
Schizencephaly
Cleft in the brain, open or closed
76
Lissencephaly
Smooth brain
77
Pachygria
Big gyri
78
Hemimegalencephaly
one side of the brain is bigger than the other
79
Hydranencephaly
More fluid than tissue in the brain can become cystic
80
Perinatal stroke
- cerebral injury of vascular origin occurring between 20 weeks GA and 28 days postnatal
- arterial ischemic stroke, cerebral venous thrombosis, and primary intracerebral hemorrhage
- common cause of acute neonatal encephalopathy
- presents as seizures in the neonatal period
81
Cerebral palsy
- a group of disorders that affects a person's motor movements
- it is secondary to abnl brain development or damage to the developing brain that affects a person's ability to control his or her muscles
- PHYSICAL disability and is STATIC (if these things are not true consider alternate diagnosis
82
Congenital cerebral palsy
- the majority of children are born with CP, usually detected around 12-18 months
- Reasons: genetic abnormalities, congenital brain malformations, maternal infections/fever, fetal injury
83
Acquired cerebral palsy
- a smaller population, event that occurs in the first 3 years of life
- Reasons for acquired CP: meningitis/encephalitis, stroke, head injury (fall, MVC, NAT)
- hemorrhage in the ventricles/scar tissue around them (choroid plexus bleeds easily)
84
Brain description of acquired cerebral palsy
1. Periventricular leukomalacia: injury of the cerebral white matter that occurs in a characteristic distribution around the ventricles
2. Intraventricular hemorrhage
3. Hypoxic ischemic injury: more global injury
85
Types of spastic cerebral palsy: pyramidal effects
1. Hemiplegia: arm, body, and leg affected on one side
2. Diplegia: Legs affected more that arms
3. Quadriplegia: whole body affected
86
Common presenting areas for pediatric tumors
1. Posterior fossa tumors: nausea, vomiting, HA, abnl gait, and coordination
2. Brainstem tumors: abnl gait and coordination, CN palsies
3. Spinal cord tumors: back pain, weakness, abnl gait
4. Supratentorial and central tumors: symptoms are generally nonspecific, most commonly HA
87
The most common malignant brain tumor of childhood:
Medulloblastoma exclusively in the cerebellum
88
Pediatric pineal tumors
- rare
- 1-12 years old
- germ cell tumors also found here
89
Pediatric pituitary tumors
- Pituitary adenoma most common
- symptoms related to hormonal disturbances
- Presentation seen: gigantism or acromegaly
90
What presents with Leukocoria?
(no red reflex) Usually seen with retinoblastoma. occurs in the first year of life (10-15% of tumors that do). diagnosed before age 2.
91
Retinoblastoma in children
- Fatal if untreated
- Survival today is 95% but treated with enucleation (removal of the eye)
92
Transverse myelitis
- rare acquired auto-immune neuro-immune spinal cord disorder
- other neuro-inflammatory disorders: ADEM, MS, neuromyelitis optica, acute flaccid myelitis (polio-like immune response
93
Peripheral nerve injuries/disorders in children
- Plexus injuries (brachial plexus injuries-- Erb palsy (C5-C6 roots)
- CMT peripheral nerve demyelination
- High arched foot (pes cavus) is most common presenting feature
94
Why do you not give babies under 1 honey?
Botulism
95
Pediatric migraines
- at all ages
- last 2-72 hours
- bilateral appearance
- photophobia and phonophobia
- other child variants: cyclic vomiting, abnl migraines, hemiplegic migraines, Alice in Wonderland syndrome, confusional migraines
96
Risk factors for autism
1. genetic (heritability 40-90%)
- Rett syndrome
2. prenatal factors
- advanced maternal/paternal age
- maternal metabolic conditions (diabetes, HTN, obesity)
3. In utero exposures
- Valporate
- Maternal infections
- Pollution
- Pesticides
- Alcohol
4. Perinatal
- low birth weight
- preterm delivery
97
Criterion A for diagnosing autism: verbal communication
Neurotypical: babbling --> single words --> 2 word phrases --> sentences
Level 1: mild speech/language delay
Level 2: moderate speech/lang delay, mix of meaningful speech and echolalia
Level 3: no meaningful verbal communication ( echolalia without social intent)
98
Criterion A for diagnosing autism: nonverbal communication
Neurotypical: eye contact --> pointing --> gestures --> joint attention
Level 1: capacity for eye contact, unclear point with index finger, overlearned gestures (high 5), variable joint attention
Level 2: little eye contact, cannot follow pointing by others, lack typical gestures
Level 3: lack of eye contact, lack of communicative gestures, lack of joint attention
-- focus on objects over faces
99
Criterion A for diagnosing autism: Social interaction
Neurotypical: inviting others to play, holding conversations, responding to social bids, resolve conflict
Level 1: difficulty initiating social interaction and having reciprocal conversations
Level 2: reduced response to others' social bids, interactions focused on special interests, unable to resolve conflict with peers
Level 3: very limited initiation of social interactions, only to meet their own needs, unusual interations
100
Criterion A for diagnosing autism: Play
Neurotypical: conventional play --> functional play --> basic imaginary play --> complex imaginary play (house roles)
Level 1: delayed play skills, imaginary play without involving others, overabsorption in play involving special interest
Level 2: Overly routinized play, repetitive play
Level 3: Lack of play skills (repetitive dumping of toys)
101
Criterion B for diagnosing autism: Routine/transitions
Neurotypical: able to follow adult-directed routines, minimal distress with transition
Level 1: inflexibility in behavior causes struggling in 2+ contexts, difficulty switching activities
Level 2: inflexibility noticeable to the causal observer, evident distress with changing activities
Level 3: severe anxiety/behavioral struggles when out of routine or transitions
102
Criterion B for diagnosing autism: stereotyped behavior
Neurotypical development: occasional stereotyped behaviors occur early in toddlerhood through the preschool years (hand flapping when excited, occasional tiptoe walking)
Level 1: Stereotyped patterns, usually involving hands/wrist during excitement or distress
Level 2: Stereotyped patterns more frequently observed across a variety of contexts
Level 3: stereotyped patterns frequently observed- echolalia, play is highly repetitive, causal observer would notice, posturing
103
Criterion B for diagnosing autism: Sensory processing
Neurotypical: mouthing items, tolerating new things
Level 1: preference for certain textures, mild avoidance or adverse sensory aspects
Level 2: Strong patterns of preference, avoidance
Level 3: Significant reactions to sensory input that interferes in ability to engage in daily routines and activities (screaming and covering ears with vacuum cleaner, gagging when certain food is put on their plate)
104
Intellectual inpairment
- deficits in intellectual functioning and adaptive functioning
- 1-3% prevalence
- 33% of children with ASD
105
Early start Denver model (ESDM)
- combo of developmental theory, ABA, and relationship focus leading to a greater improvement in social and developmental skills
106
SMBA- Kennedy's disease
- CAG repeats expanded in the Androgen receptor gene causative of spinal and bulbar muscular atrophy
- X-linked
107
Anticipation
- younger onset and increased severity in successive generations
- increasing amount of repeats, somatic and germline mosaicism
- Hairpins in CG rich sequences
- paternal bias increases mitotic divisions in spermatogenesis or alterations in DNA repair
108
PolyQ diseases
- CAG expansions in host genes with different fxns
- Late onset: no natural selection against devastating late stage disease
- act in dominant toxic manner: Proteinopathies
109
SMBA
- Androgen receptor
- size: 40-62
- Testosterone-activated steroid receptor
110
Huntington's disease (HD)
- Huntingtin protein
- size: 36-121
- possible scaffolding protein linked to diverse cellular pathways
111
DRPLA
- Atrophin-1
- size: 49-88
- Possible transcriptional corepressor
112
SCA 1, 2, 3, 7
- Ataxin- 1, 2, 3, 7
- Ataxin 1: transcriptional corepressor involved in transcription regulation, cell specification, and synaptic activity
- Ataxin 2: component of RNA processing and translational regulation pathways
- Ataxin 3: deibiquinating enzyme involved in protein quality control
- Ataxin 7: component of histone acetyltransferase complex and transcriptional regulation pathways
113
SCA6
- P/Q type calcium channel subunit alpha-1A
- large protein, 20-33
- voltage sensitive calcium channel subunit
- lower threshold for disease (only 20Q repeats)
114
SCA17
- TATA-box-binding protein
- 47-63
- Component of core transcriptional complex TFIID
115
Mechanism of Huntington's disease
Toxic convergence of Glut and Dopa on spiny neurons (BG) --> hyperexcitability, high metabolic rate, Ca2+ toxicity. Primarily affects striatum but also has widespread cortical degeneration
116
Mechanism of many SCAs
Purkinje cell susceptibility --> tonic activity
117
Huntington's Disease Triad
1. Motor hyperactivity (chorea)
2. Cognitive impairment (attention and emotion)
3. neuropsychiatric features (apathy and blunted affect)
118
Adult vs Juvenile symptoms in Huntington's disease
Adult:
- 36-60 CAG repeats
- progressive pathology (predictable)
- Caudate/putamen--> cerebral cortex --> other regions
Juvenile:
- >60 CAG repeats
- widespread pathology
- Progression is variable
119
What is the main pathology of Huntington's disease?
- atrophy of striatum and other subcortical regions --> cortical grey matter --> subcortical white matter
- prominent loss of spiny medium neurons in striatum and cortex
- Nuclear inclusions (brown aggregates)
120
Huntington's disease treatment
Tetrabenazine for chorea: synaptic vesicular amine transporter inhibitor
121
Spinocerebellar ataxias (SCAs)
- Most common: SCA3 > SCA2 > SCA1 > SCA 7
- Progressive cerebellar and brainstem degeneration: unsteady gait, clumsiness, dysarthria, pyramidal/extrapyramidal signs, ophthalmoplegia, cognitive impairment
- onset: 30s-40s depending on length of CAG repeats
122
SCA pathology
- cerebellum atrophied
- Brainstem lesions
- nuclear inclusions (brown)
123
SCA treatment
- Rehabilitation, PT, OT, speech therapy
- future treatment: anti-sense oligonucleotides that cause allele-specific degradation of the CAG repeat
- SCA1: Harry Orr, TCs)
124
PolyQ diseases
-Proteinopathies
- prone to aggregation, amyloid-like deposits of the disease protein: nuclear inclusions
- the longer the expansion, the more robust the aggregation
- prone to adopt beta sheet --> form amyloids through nucleation-seeded polymerization: prion-like behavior
125
Systems that normally keep cellular proteostasis under control
1. Chaperones: sequestration = bad
2. UPS systems: accumulation of ubiquinated mutant HTT--> impaired proteasome activity and ERAD dysfunction
3. Autophagy: impairment of fxn, inactivation of mTOR, blockage of autophagy regulation by ataxin 3
126
Fragile X- loss of function
- most common inherited form of intellectual disability + autism
- FMR1 gene frailty near the end of chromosome
- Polymorphic CGG repeat in the 5'UTR of exon 1
127
Genetics of Fragile X
-intermediate: 45-54 repeats, premutation: 55-200 repeats, Full mutation: >200 repeats --> promoter methylation of FMR1 which is an RNA binding protein --> reduced the shuttling of mRNAs
128
FMRP function
methylation in early embryogenesis --> histone changes --> gene silencing --> absence of FMRP protein --> normally FMRP is a Selective RNA binding protein--> stalls ribosomes on target mRNA near dendritic spines
Phosphorylated by S6K1 --> ubiquitinated and degraded --> LOF FMRP --> increased translation of target mRNA --> synaptic transmission --> plasticity (bad)
-- resulting in developmental problems in synapse stability and overall brain connectivity
129
Fragile X treatments
- FMRP LOF: no translation stalling --> local protein synth overactive by mGluR stimulation
-- reduce stimulation with mGluR5 antagonists to improve speech, stereotypic behavior, and hyperactivity
-- GABA agonists may help
130
Friedreich Ataxia -Loss of function
- most common hereditary ataxia (autosomal recessive)
- GAA triplet repeat intron of Frataxin gene
- onset 5-15 years old
- Symptoms: ataxia, gait, dysarthria, cardiomyopathy, daibetes
- degeneration of cerebellum, spinal cord, and peripheral nerves
131
Mechanism of Friedreich ataxia
- FXN encodes a mitochondrial protein --> Fe+-S clusters that are key for respiratory chain (energy metabolism)
- treament: release silencing --> histone deacetylase (HDAC inhibitors) and nicotinamide
132
Myotonic Dystrophy (DM1) - gain of function
- Dominant neuromuscular disorder
- CTG repeat expansion in 3'UTR of the dystrophia myotonica-protein kinase (DMPK) gene
- >38 CTG is pathological, >1500 is severe congenital
- onset and severity is determined by amount of repeats
133
Myotonic Dystrophy (DM1) - gain of function SYMPTOMS
- progressive muscle wasting
- myotonia
- cardiac arrhythmia
- cataracts
- insulin resistance
- cognitive impairment
- somnolence
- behavioral disturbances
134
Myotonic Dystrophy (DM2) - gain of function
- Autosomal dominant: CCTG expansion of intron 1 of CNCB gene
- expansions anywhere from 75-11,000 CCTG repeats
- similar symptoms to DM1
135
DM1 toxic mechanisms
DNA repeat expansion --> mRNA nuclear accumulation --> toxic RNA --> gain of fxn mechanisms
- CUG/CCUG repeats forming hairpins --> RNA-binding proteins have a high affinity for CUG repeats --> musclebind (MBNL1-3) everywhere --> depletion of MBNL --> mRNA mislocalization and miRNA misprocessing
136
FMR1 premutation: FXS RNA toxicity
- progressive parkinsonian tremor, ataxia, cognitive deficits
- Male development of FXTAS: FXS LOF of FMR1
- Female development of FXTAS: RNA GOF
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SCA8
- atypical locus
- bidirectional transcription --> nuclear foci and poly Q
- removing ATG still expresses the polyQ --> but 3 homopolymeric products: polyQ, polyA, polyS --> translation in 3 ORFs (reading frames)
138
RAN transmission
- Repeat associated non-ATG translation
- translation ALL reading frames from ATG missing --> + immunostaining with PolyQ antibodies
- Tertiary RNA structure drives RAN translation
- simultaneous pathologies: full protein with polyQ + RNA nuclear foci + RAN proteins
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Neurocutaneous disease
- Congenital inherited disorders manifested in skin and nervous system
- Phakomatoses (birthmark)
- Major cause of congenital disorders in children: intellectual disability, epilepsy, autism, psychiatric disorders
- Eye problems, benign tumors, and malignant tumors
140
What is the origin of neurocutaneous diseases?
- neural crest
- lineage including: melanocytes (skin, eye), schwann cells, chromaffin cells in medulla, glomus cells (vascular), leptomeninges
141
Von Hippel-Lindau
-pVHL: constituent of ubiquitin ligase, degradation of hypoxia-inducible factor (HIF1)
- autosomal dominant
- loss of fxn of pVHL causes abhorrent cell growth and survival
- lesions: skin, fibromas, vascular, eye, brain, renal, lung, cancer (breast)
142
Heterozygosity
- all carriers at risk of developmental disorders --> macrocephaly
- diseases: NF1, tuberous sclerosis, PTEN hamartoma
143
Two-hit genetic mechanism
- inherited (1) + somatic mutation (1, recessive)
- high frequency, presents as autosomal dominant
-Diseases: NF1, tuberous sclerosis, PTEN hamartoma, VHL
144
Somatic mutation
- 1 or 2 acquired mutations (not inherited)
- low frequency, focal presentations
-Diseases: NF1, tuberous sclerosis, PTEN hamartoma, VHL
145
Example of dominant somatic mutation
- Sturge Weber syndrome (port wine stains)
- Early progenitor mutation: worse prognosis, expansion through tissues (brain, eye, skin)
- Later progenitor mutation: better prognosis, isolated port wine stain in skin only
146
Brain symptoms of NF1
- Macrocephaly
- Hyperplastic proliferation
- occasional low grade gliomas
- Neurofibromin: expressed in projection neurons and oligodendrocytes. Astrocytes lack NF, but can be induced after injury
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Brain symptoms of Tuberous sclerosis
- 80-90% have cortical tubers (dysplasia)/ subependymal calcified nodules
- severity correlates with seizures and intellectual deficits
148
Brain symptoms of PTEN hamartoma (PHTS)
- intracranial venous abnormalities
- Developmental delay, autism, seizures, hypotonia
149
Brain symptoms of Sturge Weber
- cortical calcifications
-enlargement of the choroid plexus
- abnormal veins
- second to injury from venous stasis and poor perfusion
- enlarged, dilated leptomeningeal vessels
- Cortex: atrophy with deposition of calcium around blood vessels. number of cortical draining vesssels is decreased
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Brain symptoms of Von Hippel-Lindau
- Vascular lesions, plasma leakage, tissue edema and cysts
- CNS neoplasms below the tentorium
- hemangioblastomas in cerebellum, brainstem, spinal cord, and retina
151
Eye lesions in NF1
- Lisch nodules (iris hamartomas, benign)
- Optic gliomas in infant patients
- Benign, low grade astrocytomas: optic nerve, optic chiasm, optic tract, hypothalamus
152
Hamartoma:
noncancerous tumor made of an abnormal mixture of normal tissues and cells from the area in which it grows
153
Eye lesions in Tuberous sclerosis
- Retinal hamartomas (astrocytic, 30-50%)
- Retinal astrocytomas (more aggressive)
154
Eye lesions in PTEN Hamartoma PHTS
- corneal nerve hypertrophy
- Pseudopapilledema, amblyopia (lazy eye), strabismus
- occasionally myopia and cataracts
155
Eye lesions in Sturge-Weber
- Glaucoma in 15-20%
- Congenital or before 2 years old in 60% (EMERGENCY)
- Buphthalmos (enlargement of the globe)
- Later onset--> painless, progressive visual field loss
- Major source of morbidity, early treatment critical to improve vision
156
Eye lesions in Von Hippel-Lindau
- Hemangioblastomas in 60%
- Edemas, hemorrhage, blindness
- Skin lesions (rare)
157
What diseases do you see Nevus anemicus (loss of pigmentation)?
NF1, VHL
158
In what disease do you see glomus tumors?
NF1
159
Neurofibromas in NF1
- affect Schwann cells, perineural cells, fibroblasts, and mast cells
- Large neurofibromas --> soft tissue and bony hypertrophy --> disfigurement
- Malignant peripheral nerve sheath tumors in 10% (neurofibrosarcoma)
160
Skin lesions in NF1
- Cafe au lait spots
- excessive freckling in skin folds
- Hypomelanotic macules
161
Skin lesions in Tuberous sclerosis
- Hypomelanotic macules (90%)
- Hamartmatous mucocutaneous lesions
- Facial angiofibromas (Common)
162
Skin lesions in PTEN hamartoma PHTS
- pigmented macules in genitalia, lipomas, and vascular anomalies
- early "second hit" --> born with segmental overgrowth, verrucous epidermis, and vascular malformations
- PTEN LOF in sporadic cancers, including neural lineage
- increased risk of malignancy, particularly breast, thyroid, endometrial, colon, and renal carcinomas
163
Treatment of NF1, PTEN, TSC
-mTOR inhibitors: sirolimus (rapamycin) and everolimus
- Rapamycin analogs for glioma and vascular lesions
- Oral for renal, pulmonary, and astrocytomas
- Topical for skin lesions, no systemic absorption
164
Treatment for NF1
- mTOR inhibitors
- Lovastatin in children with learning deficits
- Potent inhibitor of RAS/mitogen-activated protein kinase (MAPK)
165
Treatment of Sturge-Weber
- symptomatic
- Control of seizures: anticonvulsants (phenobarbital), refractory epilepsy may require surgical intervention
- Low-dose aspirin for vascular congestion and thrombosis
166
Treatment for Von Hippel Lindau
- surgical resection and radiotherapy
167
HPA axis
- hypothalamic-pituitary-adrencortical axis
- CRH from hypothalamus--> ACTH from pituitary --> Cortisol from adrenal gland --> all over the body
168
Allostasis
- the process by which the body responds to stressors in order to regain homeostasis. The body only compensates for so long before it says a new baseline (higher BP example)
- excessive allostatic load --> wear and tear --> disease
169
What is trauma?
- Exposure to actual or threatened death, serious injury, or sexual violence in one or more of the following ways
1. directly experiencing the traumatic event
2. witnessing in person, the event
3. learning that the traumatic event occurred to a close family member or friend
170
Early Life Adversity (ELA)
- physical, emotional, or sexual abuse and neglect
- community and family violence before 18 years old
- leads to chronic states of stress with heavy consequences on health from generation to generation
171
Early life adversity (ELA) is associated with:
- 50% drug abuse
- 54% current depression
- 65% alcoholism
-67% suicide attempts
- 78% IV drug use
172
PTSD symptoms
- re-experiencing the trauma
- avoidance of things that remind one of the trauma
- increased tenseness and heightened awareness
Diagnosis: duration and disturbance is more than one month and causes significant impairment in function
173
Risk factors for PTSD
- physiological vulnerability
- early life adversity
- "dose" of trauma
- lack of social support
- pre-existing psychiatric disorder
174
Neurochemical correlates of PTSD
1. increased CRH
2. increased catecholamine/NE release
3. decreased serotonin
4. decreased GABA and increased glutamate
5. decrease in neuropeptide Y
6. decreased endogenous opiates
175
Comorbidities of PTSD
- depression
- anxiety disorders
- substance use disorders
- somatization
- dissociative disorders
176
Acute stress disorder
- similar exposure as in PTSD
- duration of disturbance is 3 days to one month after trauma
- causes significant impairment
177
Screening questions for stress disorders
- Have you experienced a panic attack? (PANIC)
- Do you consider yourself a worrier? (GAD)
- Have you ever had anything happen that still haunts you? (PTSD)
- Do you get thoughts stuck in your head leading to repetitive or bothersome behaviors? (OCD)
- When people observe you do you feel nervous and worry that they will judge you? (SAD)
178
Treatment options for PTSD and stress/trauma disorders
- CBT (most effective)
- Education and stress inoculation training
- Behavior therapy
- Exposure therapy
- critical incident debriefing immediately following the trauma
Pharmacological:
- SSRIs (fluoxetine)
- TCAs (imipramine)
- Benzodiazepines (alprazolam)
- Beta-blockers, clonidine, prazosin, gabapentin
179
Unipolar depression
- major depression without history of hypomania
- lifetime incidence is 15% with women being more common than men
- NTs in MDD: monoamines (DA, NE, 5-HT), glutamate, GABA, peptides, endogenous opiates
- Treatment: SSRIs (fluoxetine, sertraline, paroxetine, citalopram, escitalopram)
180
What drug is used for OCD?
Fluvoxamine
181
SSRI side effects:
- Nausea
- diarrhea
- Sexual dysfunction
- weight gain/loss
- agitation/sedation
- insomnia
- drug withdrawal (esp paroxetine)
- Hyponatremia (rare)
- Citaopram/escitalopram (QTc prolongation)
182
SNRIs
- Venlafaxine
- Desvenlafaxine
- Duloxetine
- Levomilnacipran
183
SNRI side effects
- Nausea
- anticholinergic effects
- Drug interactions
- tremor
- withdrawal
- Diastolic hypertension
184
Atypical antidepressants
-Mirtazapine
- Vilazodone
- Vortioxetine
- Trazadone
- Nefazodone
MECH: serotonin reuptake inhibition, mixed receptor agonist/antagonist
185
Drugs that have SRI effects and 5-HT receptor modulators
- Vilazodone (5-HT1A partial agonist)
- Vortioxetine ( 5-HT1A, 5-HT1B agonists, 5-HT7, 3, and 1D antagonist)
- both have minimal weight gain and sexual dysfunction
186
NE and 5-HT receptor modulators
- Mirtazapine: blocks presynaptic NE/5HT autoreceptor, and postsynaptic 5HT2/5HT3 receptor
- Low sexual dysfunction
- very sedating
- weight gain
- low incidence of nausea (5-HT3 blocker)
-
187
Desyrel
- serotonin agonist/antagonist
- SRI and 5HT2 antagonist
- very sedating, orthostasis, priapism, nasal congestion
- Rarely used
188
Nefazodone
- serotonin agonist/antagonist
- 5HT reuptake blockade, 5HT2 receptor blockade
- HEPATIC FAILURE, many DDIs
189
Bupropion
- NE/DA reuptake inhibitor (NDRI)
- used for smoking cessation, MDD, dysthymia, NOT bipolar
- SE: anticholinergic, seizures, tremor, not as bad for sexual dysfunction
- Always ask about seizure, ED, or TBI hx
190
NMDA receptor antagonists
- Dextromethorphan + bupropion
- large first pass
- Ketamine is also an NMDA receptor antagonist
191
Activating vs sedating antidepressants
Activating: fluoxetine, bupropion
Sedating: paroxetine
192
How long should you treat someone with a single episode of MDD?
6-12 months
193
When to refer to therapy
- exacerbating stressful life events
- prolonged bereavement
- concurrent PTSD, ED, PD, or OCD
- Augmentation of antidepressant therapy
194
When to refer to psychiatry
- Bipolar
- psychosis
- SI (ER)
- hx of suicide attempts
- failure of 2-3 antidepressants
- Concurrent psychiatric disorder
- sever depression (poor intake and functioning)
195
Tricyclic antidepressants
- SNRI (imipramine, desipramine, amitriptyline, nortriptyline, protriptyline, amoxapine, doxepin, clomipramine)
- Used for: MDD, dysthymia, panic disorder, pain (ami/nortrip)
- SE: anticholinergic, orthostasis, QTc prolongation, heart block, seizures, weight gain
- lethal overdose over 2 grams
- useful blood level testing possible
196
Monoamine oxidase inhibitors (rare to use)
- Phenelzine
- Tranylcypromine
- Isocarboxazide
- Selegeline (also for Parkinson's)
- they all increase 5HT, DA, and NE
- SE: HTN crisis, serotonin syndrome, orthostasis, insomnia, weight gain, sexual dysfunction
197
Dietary restriction with MAOIs
Tyramine- causes HTN crisis increased risk
198
Generalized anxiety disorder
- Chronic worry about everyday matter with physical symptoms (sweaty palms, palpitations, GI symptoms)
- Treatment: psychotherapy, SSRIs, buspirone, benzodiazepines, gabapentin
199
Buspirone
- 5HT1a partial agonist
- SE: Ha, dizziness, nausea
- very safe
200
Benzodiazepines
-DFLAT
- short course, temporary until the primary medication becomes effective
- lorazepam also used for treating alcohol withdrawal in those with hepatic failure (not metabolized by liver)
201
Panic disorder
- symptoms seem like cardiac event
- Treatments: SSRI, SNRI, TCA, MAOI, propranolol
- benzos for severe agoraphobia short course
202
Treatments for PTSD
- SSRIs
- Prazosin
- Cyproheptadine (nightmares)
203
OCD treatment
- GOLD standard: exposure therapy with response prevention
- Meds: SSRIs, clomipramine (TCA)
- takes at least 10 weeks to see effect
204
Treating tobacco addiction
- Bupropion
- Varenicline (partial nicotinic agonist)
- Nicotine replacement
205
Treating alcohol addiction
- Disulfiram (blocks aldehyde reductase)
- Naltrexone
- Acamprosate (enhances GABA)
- gabapentin
206
Treating opiate addiction
- Naltrexone
- methadone
- buprenorphine
- suboxone
207
Bipolar disorder treatments
- Lithium (gold standard)
- Valproate
- Carbamazepine
- Lamotrigine (depression mostly)
208
ADHD treatments
- Stimulants
- Atomoxetine (no abuse potential)
- alpha blocker (guanfacine)
209
Schizoaffective disorder
1. Bipolar type: psychosis and bipolar symptoms that don't always occur at the same time
2. Depressed type: psychosis and depression symptoms that don't always occur at the same time
- Treat like bipolar disorder or depression plus an antipsychotic at varying doses
210
Depression with psychotic features
- Delusional depression
- psychosis only occurs during depressive episodes
- higher SI rate, harder to treat
- treated with antidepressant and antipsychotic
- Sometimes only responds to ECT
